Apoptosis, or programmed cell death, is a physiological form of cell suicide that critically regulates the development and homeostasis of the immune system. Defects in the removal of self-reactive or damaged lymphocytes are thought to lead to autoimmune disease and leukemia/lymphoma. Therefore, understanding the signaling pathways involved in lymphocyte apoptosis remains an important challenge. Mice doubly-deficient in Bax/Bak (DKO), two proapoptotic BCL-2 family members, have been generated and largely die in utero. DKO mouse embryonic fibroblasts or fetal-derived lymphocytes reconstituted into Rag-1-/- mice are strikingly resistant to apoptosis in response to a wide range of death stimuli, including signals specifically targeting the endoplasmic reticulum (ER). While originally shown to work by receiving activated BH3 proteins at mitochondria, preliminary studies strongly suggest that BAX/BAK play a second role in maintaining ER Ca2+ stores and controlling Ca2+ signaling between the ER and mitochondria. Based on these results, this proposal intends to understand how BAX/BAK control ER Ca2+ stores and what role this plays in their regulation of mitochondrial-dependent apoptosis. [unreadable] [unreadable] Specifically, the project aims to: 1) Define the contribution of ER-derived Ca2+ in cell death in fibroblasts, 2) Determine the mechanism by which proapoptotic BAX/BAK regulate Ca2+ signaling between ER and mitochondria, and 3) Determine how BAX/BAK deficiency affects Ca2+-dependent signaling in T lymphocytes. Further work will define the signaling pathways controlling cell death in the immune system to gain fundamental insight into the pathogenesis of autoimmunity and cancer. [unreadable] [unreadable] Dr. Scott Oakes, the Principal Investigator, is an M.D., who has completed residency training in anatomic pathology, and wishes to develop an independent research career focusing on the molecular pathways of apoptosis and how they relate to human disease. The sponsor, Dr. Stanley J. Korsmeyer, is a world-leader in the field of apoptosis with a strong record of training successful basic investigators. [unreadable] [unreadable]